Chroman derivatives



United States Patent This invention relates to new and useful compounds in the field of organic heterocycle chemistry. More particularly, it is concerned with various novel 2- guanidinoalkylchromans which have been found to be useful as therapeutic agents in view of the biological properties which they possess.

The compounds which are included within the purview of the present invention are all selected from the class of organic bases having the following general structural formula:

NR R s \O 5 NR 0 NHR7 and the mineral and organic acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen, chlorine, bromine, iodine, alkyl and alkoxy each having up to six carbon atoms; R R R and R are each a member selected from the group of hydrogen and alkyl containing up to six carbon atoms; X is a member selected from the group consisting of (CH CH- NH and CH CH NH wherein n is an integer of from one to four; and each of R and R represent members chosen from the group consisting of hydrogen, alkyl containing up to six carbon atoms, acyl derived from a lower fatty acid containing from two to six carbon atoms, and when taken together with the nitrogen atoms to which they are attached, form part of a heterocyclic ring. It is to be noted that the substitucnt R may be situated at any available position in the benzene ring. These compounds are all of value inthe treatment of hypertension,

Of especial value in this connection, and as a matter of fact the preferred compounds of this invention, are those of the formula:

and the mineral and organic acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl and lower alkoxy; R R and R are each a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of lower alkylene, CH NH and CH CH NH; and each of R and R are members chosen from the group consisting of hydrogen and lower alkyl and, when taken together with the nitrogen atoms to which they are attached and the carbon atom which is geminal to said nitrogen atoms, imidazolinyl. Typical member compounds of the this series include such compounds as Z-guanidinomethylchroman, 2-guanidinomethyl-3-methylchroman, 2-(3- guanidinopropyl)chroman, 2 guanidinoaminomethylchroman, 2 (l methylguanidino)methylchroman, 2- guanidinomethyl 7 chlorochroman, 2 (N,N'-ethyl- 3,33fi38 Patented July ll, 1967 eneguanidinomethyl)chroman, and the like. These compounds are all potent regulators of the cardiovascular system and, as previously indicated, are especially active as anti-hypertensive agents, in addition to being equally effective as adrenergic neurone blocking agents.

The process employed for preparing the novel compounds of this invention involves treating an appropriately substituted 2-aminoalkylchroman compound with a suitable S-alkyl isothiouronium salt having the requisite substituent groups. This particular reaction is normally carried out in a reaction-inert polar solvent medium at a temperature ranging from about 20 C. up to about 120 C. for a period of about four to about 72 hours, and most conveniently at a temperature ranging from about 60 C. to about C. for from about 4 to 20 hours. In practice, it is generally most convenient to heat the two reactants together under refluex in the polar solvent, employing substantially equimolar amounts of starting maaterials for this purpose although a slight excess of one or the other is not harmful in this respect. The desired S-alkyl isothiouronium salt reagent, of course, is preferably one where the S-alkyl group is lower alkyl in view of relative ease with which such a reaction takes place due to the more volatile nature of the by-products produced, i.e., the lower boiling mercaptans. Preferred reaction-inert polar solvents for use in this connection include water, lower alkanols, such as methanol, ethanol and isopropanol, etc., and N,N-di(lower alkyl)alkanoamides such as N,N- dimethylformamide, N,N- dimethylacetamide, N, N diethylformamide, N,N diethylacetamide, N,N di(npropyl)formamide, N,N-dimethylpropionamide, and so forth, as well as mixtures of either of these two aforementioned type organic solvents with water. Upon completion of the reaction, the solvent is removed by means of conventional procedures and the resulting residue taken up in a suitable solvent system, such as one of the aforementioned types, from which it can be subsequently crystallized. Alternatively, the product may separate first from the reaction mixture either during the course of the reaction or immediately thereafter, or it may be crystallized from the reaction solution after some initial concentration of same. A final conversion to the desired organic base compound can then be efiected by treating the Z-guanidinoalkylchroman acid addition salt thus obtained with sufiicient base in water to neutralize same, e.g., an alkaline reagent such as sodium hydroxide in water can be used. Recovery of the desired free organic base can then be had by extracting the aforesaid aqueous solution with a suitable water-immiscible organic solvent of low volatility, such as a halogenated aliphatic hydrocarbon solvent like methylene chloride, for example.

The starting materials necessary for the above reaction process are either all known compounds or else they are easily prepared by those skilled in the art in accordance with standard organic procedures. For instance, the 2- aminoalkylchromans required for conversion to the guanidines can easily be prepared by known routes starting from the corresponding carboxylic acid amides which are, in turn, prepared from the chroman-Z-carboxylic acids themselves. The amides are then converted to the amines by standard reductive methods for these purposes. The carboxyilic acids concerned are obtainable by routes of themselves well-known in the art like that of Baddeley and Cooke, for example, as described in the Journal of the Chemical Society, p. 2707 (1958) for the preparation for chroman-Z-carboxylic acid. Needless to say, the corresponding S-alkyl isothiouronium salts, such as S-methyl isothiouronium sulfate or hydrochloride or N,N',S- trimethyl isothiouronium hydriodide, for example, are all members of a well-known class of organic compounds.

Other methods which can be used to prepare the novel compounds of this invention include routes not involving the use of the S-alkyl isothiouronium intermediates and these are as follows: (1) the reaction of a 2-sulfonyloxyalkylchroman compound with the appropriate guanidine salt to afford the corresponding Z-guanidinoalkylchroman salt direct; (2) the reaction of a Z-aminoalkylchroman compound with a salt of the appropriate guanylpyrazole base, such as 3,5-dimethyl-l-guanylpyrazole, to also form the corresponding Z-guanidinoalkylchroman salt; (3) the reaction of a Z-aminoalkylchroman salt, such as a hydrohalide, with a cyanamide like the parent compound itself or an appropriately substituted derivative thereof or by fusion reaction of said amine salt with a dicyanamide compound to also form the corresponding Z-guanidinoalkylchroman salt direct; and finally, (4) the reaction of a Z-aminoalkylchroman compound with a cyanogen halide, like cyanogen bromine, followed by the reaction with the resultant intermediate N-cyano product with ammonia or with an appropriate amine to form the corresponding Z-guanidinoalkylchroman base.

Of all these alternate routes, the most preferred one is the previously mentioned process involving the reaction of a 2-aminoalkylchroman compound, such as Z-aminomethylchroman, with a salt of the appropriate guanylpyrazole base to form the corresponding Z-guanidinoalkylchroman salt direct. The preferred reagent here is a salt of 3,5-dimethyl-l-guanylpyrazole, such as the corresponding sulfate, but it is also possible to employ other lower 3,5-dialkyl-l-guanylpyrazole salts in place of 3,5-dimethyll-guanylpyrazole sulfate and achieve equally satisfactory results as well. This particular process is generally carried out by heating the two reactants together in an aqueous solvent medium of the type previously discussed for the S-alkylisothiouronium method in the absence of any other reagent. Recovery of the desired product from the reaction mixture is then easily effected by evaporation of same under reduced pressure, followed by the subsequent crystallization of the resultant residue from either water or from an aqueous alcohol mixture.

Inasmuch as the products of most of the guanidineforming reactions are obtained in the form of their salts, the free guauidine bases can thereafter easily be obtained by treatment of said salts with a suitably strong alkaline reagent, such as sodium hydroxide, as previously indicated. The free base compounds can then be isolated from the aqueous alkaline medium by means of extraction into a suitable water-immiscible organic solvent phase, preferably employing one of the lower boiling solvents such as a halogenated hydrocarbon solvent, like methylene chloride.

Insofar as the Z-guanidinoalkylchroman compounds of this invention are basic compounds, they are capable of forming a wide variety of salts with various mineral and organic acids. Although such salts must be pharmaceutically acceptable when the final products are intended for oral consumption, it is possible to first isolate the desired Z-guanidinoalkylchroman compound from the reaction mixture as a pharmaceutically unacceptable salt and then to subsequently convert the latter, as indicated previously, to the free base by treatment with an alkaline reagent, followed by the final conversion to the pharmaceutically acceptable acid salt in the manner hereinafter indicated. For instance, the acid addition salts of the 2-guanidinoalkylchroman compounds of this invention may be prepared by treating the base compound with a substantially equimolar amount of the chosen acid. The salt-formation step can be carried out in an aqueous solution or in a suitable organic'solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned Z-guanidinoalkylchroman bases of this invention are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydriodide, nitrate, sulfate or bisulfate,

phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzeuesulfonate and p-toluenesulfonate salts.

As previously mentioned, the compounds of the present invention are all readily adapted to therapeutic use as antihypertensive agents in view of their ability to lower the blood pressure of correspondingly agitated subjects. For instance, Z-guanidinomethylchroman sulfate has been found to produce a definite antihypertensive response in animals by lowering the blood pressure of hypertensive animals to a statistically significant degree when orally administered to them. At 20 mg. per kg. of body weight, this particular compound causes an excellent relaxation of the nictitating membrane. It also lowers the blood pressure of anesthetized normotensive cats and anesthetized neurogenically hypertensive dogs in a highly satisfactory manner, while in unconscious dogs, it was found to elicit a moderately good fall (20-30 mm. Hg) in blood pressure. Furthermore, no problems of toxicity or any other untoward side effects have even been encountered with any of these compounds in their administration to animals.

In accordance with a method of treatment of the present invention, the herein described antihypertensives can be administered to an agitated subject via the oral or parenteral routes. In general, these compounds are most desirably administered in doses ranging from about 10 mg. up to about 240 mg. per day, although variations will necessarily occur depending upon the weight of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of from about 0.15 mg. to about 4.8 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results. Nevertheless, it is to be appreciated that still other variations may also occur in this respect, depending upon the species of animal being treated and its individual response to said medicament, as well as on the particular type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger dosages may be employed without causing any harmful or deleterious side effects to occur provided that such higher dose levels are first divided into several smaller doses that are to be administered throughout the day.

In connection with the use of the Z-guanidinoalkylchroman compounds of this invention for the treatment of agitated subjects, it is to be noted that they may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical compositions can be suitably sweetened and/ or flavored by means of various agents of the type commonly employed for just such a purpose. In general, the therapeutically'etfective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about by weight of the total composition, i.e., in amounts which are suflicient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection would also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particular Z-guanidinoalkylchromans in sesame or peanut oil or in aqueous-propylene glycol or N,N-dimethylformamide may be employed, as well as sterile aqueous solutions of the corresponding water-soluble, non-toxic mineral and organic acid addition salts previously enumerated. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sutficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are readily obtained by standard techniques Well-known to those in the art. For instance, distilled water is ordinarily used as the liquid diluent and the final preparation is passed through a suitable bacterial filter, such as a sintered-glass filter or a diatomaceous-earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, the Chamberland and the asbestos disc-metal Seitz filter, wherein the fluid is sucked through the filter candle into a sterile container with the aid of a suction pump. Needless to say, the necessary steps should be taken throughout the preparation of these injectable solutions to ensure that the final products are obtained in a sterile condition.

This invention is further illustrated by the following examples, which are not to be construed in any way or manner as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/ or the scope of the appended claims. In these examples, parts by weight bear the same relation to parts by volume as grams do to milliliters. Further, the percentage values expressed herein are always by Weight except where otherwise stated.

Example I 2-aminomethylchromau (2.5 g., 0.0153 mole) was dissolved in ml. of Water containing 3.2 g. of 3,5-dimethyl-l-guanylpyrazole sulfate and heated for 24 hours on a steam bath. The spent reaction mixture was then cooled slowly, diluted with 200 ml. of water and extracted (washed) with several portions of diethyl ether. The ether extracts were discarded and the aqueous layer saved and evaporated to dryness under reduced pressure to give di(2- guanidinomethylchroman)sulfate, M.P. 216220 C. after one recrystallization from isopropanol-water.

Analysis.Calcd. for C H N O S: C, 51.96; H, 6.34; N, 16.53; S, 6.29. Found: C, 51.88; H, 6.39; N, 16.30; S, 6.50.

Example II The procedure described in Example I is repeated employing 2-aminomethyl-7-chlorochroman in place of 2- aminomethylchroman on the same molar basis as before. In this particular case, the corresponding product obtained is di(2-guanidinomethyl-7-chlorochroman)sulfate.

In like manner, the use of 2-aminomethyl-6-bromochroman as a starting material in this reaction affords di(2-guanidinomethyl-6 bromochroman)sulfate as the final product.

Example 111 The procedure described in Example I is repeated with 2-aminomethyl-S-methylchroman as the starting material in place of the Z-aminomethylchrornan compound used before, but still maintaining the same molar proportions. In this particular case, the corresponding product obtained is di(2-guanidinomethyl-S-methylchroman)sulfate.

In like manner, the use of 2-aminomethyl-7-ethylchroman as a starting material in this reaction affords di(2-guanidinomethyl-7-ethylchroman)sulfate as the final product.

Example IV The procedure described in Example I is repeated on the same molar basis as before except that 2-aminomethyl-6-methoxychroman is the starting material employed in place of Z-aminomethylchroman. In this particular case, the corresponding product obtained is di(2 guanidinomethyl-6-methoxychroman) sulfate.

In like manner, the use of 2-aminomethyl-8-isopropoxychroman as a starting material in this reaction affords di(2-guanidinomethyl-8 isopropoxychroman) sulfate as the final product.

Example V 2-aminomethyl-3-methylchroman (2.65 g., 0.015 mole) and 3.2 g. of 3,5-dimethyl-l-guanylpyrazole sulfate are reacted together in 15 ml. of water in the same manner as in Example I. The corresponding product obtained in this particular case is di(2-guanidinomethyl-3 methylchroman) sulfate.

In like manner, the use of 2-aminomethyl-4- (n-propyl) chroman as a starting material in this reaction affords di [2-guanidinomethyl-4 (n-propyl)cl1roman]sulfate as the final product which is obtained.

Example VI The procedure described in Example I is repeated with Z-aminoethylchroman as the starting material of choice in place of the corresponding methyl compound, using the same molar proportions, of course. The particular product obtained in this case is di[2-(2-guanidinoethyl) chromanjsulfate.

In like manner, the use of 2-(3-aminopropyl)chroman as a starting material in this reaction affords di[2-(3- guanidinopropyl)chroman]sulfate as the final product which is obtained.

Example VII Z-hydrazinomethylchrornan (2.65 g., 0.015 mole) and 3.2 g. of 3,5-dimethyl-l-guanylpyrazole sulfate are reacted together in 15 ml. of water in the manner of Example I to afford di(Z-guanidinoaminomethylchroman)sulfate as the product which is obtained.

In like manner, the use of 2-hydrazinoethylchroman as a starting material in this reaction affords di[2-(2-guanidinoaminoethyl)chroman]sulfate as the final product which is obtained.

Example VIII 2 (N-methyl)aminomethylchroman (5.4 parts by weight) and S-methyl isothiouronium sulfate (4.2 parts by weight) in 20 ml. of aqueous ethanol are refluxed together for 48 hours. The solvent is then removed by means of distillation under reduced pressure, and the residue so obtained is crystallized first from ethanol and then from Water. In this manner, there is obtained di[2- (l-rnethylguanidino methylchroman] sulfate.

In like manner, the use of 2-(N-ethyl)aminomethylchroman as a starting material in this reaction affords di [2-(l-ethylguanidino)methylchroman] sulfate as the final product which is obtained.

7 Example IX Three and one-half parts by weight of Z-aminornethylchroman and five parts by Weight of N,N',S-trimethyl isothiouronium hydriodide in 10 ml. of aqueous dimethylene chloride, followed by separation of the organic layer and its subsequent concentration under reduced pressure then affords Z-guanidinomethylchroman as a free base.

In like manner, when each of the other Z-guanidinoalkylchroman salt compounds reported in Examples II-X formamide are warmed together on a steam bath for six 5 hours. The solvent is then removed from the reaction mixi Sublect to i Same.react1on Procedure the colrespond' ture by means of distillation under reduced pressure and mg free Organic base 15 always the Product Obtamed' the residual oil basified with 10 sodium hydroxide Example XH solution. The resulting aqueous solution is then extracted with diethyl ether and the ether extract thus obtained is 10 The o ng -g anidi oa kylchromans can be presubsequently dried over anhydrous magnesium sulfate. pared according to the procedures described in the previ- Upon removal of the drying agent by means of filtration ous examples from the appropriate starting compounds:

R3 R1 %NR -XNRC NHRI R1 R1 R3 X R5 R" R7 5-131 H H CH1 11-C3H7 H H H OH; H ciHiNH H H CH 7-oH H H 03H H H H 3 61 H CH3 03H; CH3 H ISO-C3117 H H CzH; C2115 -CHzCHz- G-CHa H H CH3 ISO-03H; H CzH5 H H CH3 03H H H H H C2115 H ctHi oHi H CH 7-C3H7 H C2H5 03115 H H II-C3H7 H H H CIfiNH ll-C H7 CH3 CH3 8-C-3Hs CH3 H CsHll H H H 50 C1H5 H Il-C3H7 CH7 CH3 C2H5 02115 6 01 H H C2H4 C2H5 CHgCHz- 7-OOH H H C3H n-C H H H H ISO-O3H7 H CzHsNH H H CH3 H H CH ciHt n CiHz H H 7-CH3 H H CH2 CH3 H H B-Bl C2H5 H C Ha H H H H H CH C3Hfl H CH -CH S-C3H7 H H CH5 H CH3 CH3 H H H CH CQHE, H CH 7-Br H CH3 CzHt CH3 H H fi-Cl H H mm H H H H H H C2114 CH3 H H and the solvent by means of evaporation, there is ob- Example XIII i g g i flflnfsubsefquenfly The non-toxic hydrohalide acid addition salts of each of 5. 1 m 3 g 5 fif i the Z-guanidinoalkylchroman bases reported previously 9 2 i i 2 8a Y in Examples XIXII, such as hydrochloride, hydrobros e W 9 32 f Y mide and hydriodide salts thereof, are individually prefi g. Pre a 2 W1 t 6 3 2 1 pared by first dissolving the respective organic base com- Is g f e 3 i 1 y S y pound in absolute ether followed by introduction of the i p gi Oman] 1 p- 0 Hey y rogen appropriate hydrogen halide gas into the reaction solua m e 0 mm E l X tion until saturation of same is complete with respect to xamp e said gas, whereupon the desired salt precipitates from Z-aminomethylchroman (four parts by Weight) and 8- solution. The crystalline product so obtained is then methyl N,N'-ethyleneisothiouronium hydriodide (six recrystallized from acetone-ether to yield the pure hydroparts by weight) in 25 ml. of absolute ethanol are rehalide salt. For instance, when 1.0 g. of Z-guanidinomethfiuxed together for six hours. The solvent is then removed ylchroman is dissolved in anhydrous diethyl ether and by means of distillation under reduced pressure, and the dry hydrogen chloride gas is subsequently passed into the residual oil which results is then dissolved in a small resulting solution until saturation of same is complete amount of ethanol and basified with 10 N sodium hywith respect to said gas, there is obtained a crystalline droxide solution. The resulting aqueous solution is then precipitate of Z-guanidinomethylchroman hydrochloride. extracted with diethyl ether and the ether extracts subse- Example XIV quently dried over anhydrous potassium carbonate and filtered. The filtrate is then concentrated under reduced filtrate, sulfate or blslllfale than those P pressure, and the residual material taken up in a minimum Vlously TeCOIded), p lf acld Phosphate, acetate, am unt f absolut thanol d dd d as h t a 1 lactate, citrate or acid citrate, tartrate or bitartrate, oxatiOn of excess l-di(p-tolu0yl)-D-tartaric acid in the same late, suecinate, maleate, glueonate, saecharate, h solvent. On standing, a solid material soon precipitates Sulfollate, ethanesulfonate, benlenesullollate and P wliieli Can be filtered and thereafter recrystallized from enesulfonate salts of each etthe l-guamdmoalkylchroman ethanol to constant melting point. In this manner, there bases prevlollsly p 111 P are all is obtained pure [2-(N,N'-ethyleneguanidinomethyl) prepared by separately dlssolvlng in a suitable amount of chroman] l-di(p-toluoyl) -D-hydrogen tartrate, ethanol the proper molar amounts of the respective acid E m 1 X1 and the appropriate organic base and then mixing the two M p 6 solutions together, followed by the addition of diethyl Ten parts by Weight of di(Z-guanidinomethylchrornan) ether to the resulting reaction solution in order to elfect sulfate in 50 parts by volume of water is neutralized with precipitation of the desired acid addition salt therefrom. 10 N sodium hydroxide solution. Extraction of the re- For instance, when equimolar amounts of 2-(3-guanidinosuiting aqueous solution with several portions of methylpropyl) -3-metl1ylchroman and concentrated sulfuric acid react in accordance with this procedure, the corresponding product obtained is di[2-(3-guanidinopropyl)-3-methylchroman] sulfate. In like manner, each of the other salts are similarly prepared.

What is claimed is:

1. A compound selected from the class consisting of organic bases of the formula:

and the mineral and organic acid addition salts thereof, wherein R is a member selected from the group consisting of hydrogen, chlorine, bromine, lower alkyl and lower alkoxy; R R and R are each a member selected from the group consisting of hydrogen and lower alkyl; X is a member selected from the group consisting of lower alkylene, CH NH and CH CH NH; and each of R and R are members chosen from the group consisting of hydrogen and lower alkyl and, when taken together With the nitrogen atoms to which they are attached and the carbon atom which is geminal to said nitrogen atoms, irnidazolinyl.

2. A compound of claim 1 wherein R R R R R and R are each hydrogen and X is lower alkylene.

3. A compound of claim 1 wherein R is chlorine, R R R R and R are each hydrogen and X is lower alkylene.

l 4. A compound of claim 1 wherein R is lower alkyl,

R R R R and R are each hydrogen and X is lower alkylene.

5. A compound of claim 1 wherein R R R R and 5 R are each hydrogen, R is lower alkyl and X is lower alkylene.

6. A compound of claim 1 wherein R R R and R are each hydrogen, R and R when taken together with the nitrogen atoms to which they are attached and the carbon atom which is geminal to said nitrogen atoms, is imidazolinyl and X is lower alkylene.

7. A compound of claim 1 wherein R R R R and R are each hydrogen, R is methyl and X is lower alkylene.

8. Z-guanidinornethylchroman.

9. 2-guanidinomethyl-3-methylchroman.

. 2-(3-guanidinopropyl)chroman.

. 2-guanidinoaminomethylchroman.

. 2-(1-methylguanidino)methylchroman.

. 2-guanidinomethyl-7-chlorochroman.

. 2-(N,N-ethyleneguanidinomethyl)chroman.

References Cited UNITED STATES PATENTS 4/1966 Augstein et al 260309.6 9/1966 Augstein et al. 260309.6 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF ORGANIC BASES OF THE FORMULA: 